tbuckley/cabot-search huggingface dataset:
GENOMIC LANDSCAPE AND ACTIONABLE MUTATIONS OF BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW
Authors: Lily Andrews, Zak Thornton, Ruqiya Saleh, Sarah Dawson, Richard Daly, Julian Higgins, Philippa Davies, Kathreena Kurian
Journal: Neuro-Oncology (2023)

Abstract AIMS Lung cancer causes the most deaths worldwide due to cancer. Non-small cell lung cancer (NSCLC) represents the largest subgroup (80-90%), with most patients presenting at an advanced stage of disease. Brain metastases (BM) develop in about 27% of these cases, leading to a poor survival outcome. Previous literature has suggested that BM derived from NSCLC have a different genomic profile compared to the primary NSCLC. We aim to review the literature to discover the genomic landscape of BM derived from NSCLC. METHOD Embase, MEDLINE, Web of Science, and BIOSIS were searched, and any records found were assessed for eligibility. For the included papers, patient information, smoking status, genomic data, matched primary NSCLC, and PD-L1 expression was extracted. RESULTS 72 papers were included in the review, with data on 2,340 patients. The most mutated genes were EGFR (n=560), TP53 (n=331), KRAS (n=328), CDKN2A (n=97), STK11 (n=72). Frequently mutated missense mutations included L858R (n=80) in EGFR and G12C (n=17) in KRAS. Ever versus never smokers were found to have differing mis- sense mutations in TP53 and EGFR, with the expectation of L858R and T790M. BM were suggested to have a different genomic landscape compared to the primary NSCLC. PD-L1 expression was found to be low in BM derived from NSCLC. CONCLUSIONS To our knowledge, this is the first systematic review which assessed the genomic landscape of BM derived from NSCLC. This review highlights the most mutated genes, missense mutations, and their clinical actionability. Differing genomic profiles were suggested in primary compared to BM and smoking status.
TUMOUR TREATING FIELDS WITH DDR INHIBITORS EFFECTIVELY LEADS TO CHEMO-/RADIO-SENSITISATION OF GLIOMAS
Authors: Callum Jones, Aurelie Vanderlinden, Katie Myers, Connor McGarrity-Cottrell, Ola Rominiyi, Spencer Collis
Journal: Neuro-Oncology (2023)

Abstract AIMS High grade gliomas are the most common CNS malignancies and cause ~200,000 deaths/year globally. Glioblastoma (WHO grade IV) confer the worst prognoses with their treatment being hindered by glioma stem cell-like (GSC) tumour sub-regions and high intratumoural spatio-heterogeneity. Tumour Treating Fields (TTFields) exert clinically approved alternating electric fields of intermediate frequency which induces anti-mitotic effects within concomitant deleterious effects on cellular responses to DNA damage (DDR). Therefore, treatment resistance could be overcome with TTFields with clinically developed DDR inhibitors (DDRi) to cause chemo-/radio- sensitisation. METHOD Surgically resected samples derived from the tumour core and invasive edge were processed to create GSC cell lines, offering highly clinically relevant models. These were grown in either 2D or in 3D-printed AlvetexTM scaffolds, treated with DDRi, subjected to chemo-/radio-therapy and then placed under TTFields (200 kHz, 48- 72 hrs). Survival was measured by clonogenic assays after 3 weeks. Immunofluorescence and western blot analysis were used to analyse the combination treatment effects on the DDR. RESULTS TTFields with DDRi led to significant chemo/radio-sensitisation in both 2D and 3D intratumoral core/edge GSC models. Western blot and immunofluorescence analyses revealed that DNA damage was heightened by the combination treatments with lesion resolution being impaired. CONCLUSIONS DDRi with concurrent TTFields effectively leads to significant chemo-/radio-sensitisation in clinically relevant 3D GSCs which model spatio-heterogeneity which is thought to impede treatment effcacy. Given that all the DDRi used are BBB penetrable and are either clinically approved or in clinical trials, TTFields could additionally compliment these treatment regimens in gliomas to boost their effcacy.
BRAIN TUMOUR GENETIC NETWORK SIGNATURES SUPERIORLY FORECAST SURVIVAL
Authors: James Ruffle, Samia Mohinta, Guilherme Pombo, Robert Gray, Valeriya Kopanitsa, Faith Lee, Sebastian Brandner, Harpreet Hyare, Parashkev Nachev
Journal: Neuro-Oncology (2023)

Abstract AIMS Gliomas typically exhibit a spectrum of genetic mutations, reflecting multiple, potentially complex interactions across distinct molecular pathways. Predicting disease evolution and prescribing individually optimal treatment plausibly requires statistical models complex enough to capture the intricate genetic structure underpinning oncogenesis. METHOD Here we formalize this task as the discovery of distinct patterns of connectivity within network representations of the interactions between genetic loci. Evaluating multi-institutional clinical, genetic, and outcome data from 4023 consecutive patients over a 14-year period, we employ Bayesian stochastic block modelling to reveal a hierarchical network structure of tumour genetic interactions spanning glioblastoma, oligodendroglioma, and astrocytoma. RESULTS We show that this structure not only identifies diagnosis but predicts patient survival with greater fidelity than the latest WHO tumour classification or linear models of genetic features. For example, a diagnosis of IDH- wildtype glioblastoma yielded median survivals varying from 289 days in patients with the signature of marked EGFR amplification, MGMT methylation, and histone mutations, to 425 days in those with the signature of TERT mutations, histone, and EGFR wild-types, and variable MGMT methylation. CONCLUSIONS Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours and show network analysis reveals distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories, paving the way for personalised prognostication.
RADIOGENOMICS FOR IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Prajwal Ghimire, Golestan Karami, Marc Modat, Thomas Booth
Journal: Neuro-Oncology (2023)

Abstract AIMS Immunotherapy is an effective precision medicine treatment for several cancers. Obtaining imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients, has the potential to identify immune biomarkers pre-operatively and allow personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the developments in bioinformatics and machine learning provide the opportunity for such developments. Therefore, we performed a systematic review of radiogenomic biomarkers for immunotherapy in glioblastoma to identify current and potential targets for immunotherapy. METHOD A systematic review was performed following PRISMA guidelines on the databases of PubMed, Medline and Embase. QUADAS 2 questionnaire was utilized for quality assessment. Qualitative analysis was performed. Insuffcient data prevented meta-analysis. PROSPERO: CRD42022340968 RESULTS Five articles were included, and all articles were retrospective studies. Biomarkers identified from MRI im- ages included apparent diffusion coeffcient (ADC) values, relative cerebral blood flow (rCBV) values and radiomic features that correlated with genomic markers from tumour cells and immune cells (tumour associated macrophages (TAMs), T cells and antigen presenting cells. Risk of Bias and applicability concerns were raised by QUADAS quality assessment. CONCLUSIONS Radiogenomic immune biomarkers are likely to provide early treatment options to patients with glioblastoma and will help improve quality of life of patients. There is a paucity of prospective studies identifying these diagnostic biomarkers, and interpretation is limited due to high risk of bias and poor generalisability . Targeted immunotherapy based on these biomarkers has the potential to allow individualised neo-adjuvant precision treatment options in clinical trials, plausibly leading to enhanced overall survival of these patients.
NON-ENHANCING/MINIMALLY ENHANCING GLIOMAS: CAN WE IDENTIFY LOW GRADE GLIOMAS?
Authors: Yuta J Saady, Richard Mair, Alexis Joannides, Thomas Santarius, Tomasz Matys, Stephen J Price
Journal: Neuro-Oncology (2023)

Abstract AIMS Gliomas are traditionally separated into low-grade (LGG) and high-grade (HGG). As LGG are slower growing and with pressures on operating capacity, there is an argument that surgery for these patients can wait. Pre- operatively, contrast enhancement on imaging is usually taken as the method of differentiating grade, with the belief that the absence of enhancement indicates LGG. We therefore assessed patients with minimal/non- enhancing tumours and compared factors at diagnosis with final histological outcome. METHOD We identified a cohort of patients over a 19-month period with a first presentation to the neurosurgical oncology clinic with minimal/patchy/scattered foci of enhancement (ME) or no areas of contrast enhancement (NE) on imaging, collecting factors at diagnosis and histological outcome using electronic patient records. RESULTS Of 60 patients identified, 53.3% were HGG, 35.0% LGG and 11.7% non-glioma. In NE tumours HGG and LGG rates were equal (43.3%), whereas in ME tumours HGG comprised 63.3% versus 26.7% LGG. HGG patients were older on average than LGG (median age 53 years versus 33 years) and more prevalent in males (62.95%) compared to females (45.45%). HGG formed the majority of patients presenting with seizure only (60%), neurological deterioration only (50%) or ≥2 symptoms (57.6%), whereas LGG was higher in presentations with headache only (66.7%) or none of the symptoms (66.7%). CONCLUSIONS It is not possible to differentiate between ‘high-grade’ and ‘low-grade’ gliomas based on imaging findings alone. Age is clearly a differentiating factor, but symptoms do not appear to be. We are working to develop methods to better differentiate these tumours pre-operatively.
SPATIAL DISTRIBUTION AND FUNCTIONAL RELEVANCE OF FGFR1 AND FGFR2 EXPRESSION FOR GLIOBLASTOMA TUMOUR INVASION
Authors: Ayesha Begum, Nawal Alshahrany, Ana Jimenez-Pascual, Florian Siebzehnrubl
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) is the most common brain tumour in adults. The GBM microenvironment is made up of heterogeneous GBM cell populations, but how microenvironmental signalling pathways contribute to GBM het- erogeneity and specific GBM pathological features remains incompletely understood. Here, we compare expression of fibroblast growth factor receptors (FGFRs) within the tumour core and the invasion front, specifically investigating the functional relevance of FGFR1 and FGFR2 for in GBM invasion in vitro and in vivo. METHOD Quantification of the relative expression levels of FGFR1 and FGFR2 was determined in GBM primary patient- derived cell lines and xenograft models. Additional transcriptional profiling using RNA sequencing identified potential gene-regulatory networks involved in FGFR1-driven GBM tumour invasion. RESULTS We found FGFR1 distributed across the tumour mass and expressed in invasive GBM cells, while FGFR2 expression is confined to the tumour mass only. Loss of FGFR1, but not FGFR2, significantly reduced cell migration in vitro and tumour invasion in human GBM xenografts. Comparative analysis of RNA-sequencing data of FGFR1 and FGFR2 knockdown GBM cells revealed a FGFR1-specific gene regulatory network associated with tumour invasion. CONCLUSIONS Differential expression of FGFR1 and FGFR2 on invasive GBM cells identified FGFR1 is functionally relevant for tumour invasion in GBM. New gene candidates linked to FGFR1-mediated GBM invasion have been revealed and warrant further investigation to identify how FGFR1 regulates GBM invasion.
CIRCULATING PROGNOSTIC BIOMARKERS IN MENINGIOMA: S100A4 AND FIBULIN-2
Authors: Sarah Kingdon, Agbolahan Sofela, Claire Adams, Oliver Hanemann
Journal: Neuro-Oncology (2023)

Abstract AIMS We aim to identify circulating prognostic biomarkers that accurately identify high risk meningioma whilst reducing the burden of invasive diagnostics. In our proteomic analysis, S100A4 and Fibulin-2 are significantly over expressed in grade 2 tumours compared to grade 1. They are both calcium-binding proteins with S100A4 involved in mesenchymal transition while Fibulin-2 helps scaffold the extracellular matrix. Elevated levels correlate with aggressive phenotypes in multiple cancers. METHOD Anonymised pre-operative meningioma blood samples were obtained from ‘The Plymouth Brain Tumour Biobank’ and ‘UK Brain Archive Information Network (BRAIN-UK)’. In total, 155 samples were analysed via Enzyme-Linked Immunosorbent Assay (ELISA) for serum S100A4 and plasma Fibulin-2. The Area Under the Receiver Operating Characteristic (ROC) curve (AUC) was used to examine the specificity and sensitivity of both markers. RESULTS Circulating levels of S100A4 were significantly (*p&amp;lt;0.05) higher in grade 2 meningiomas (mean 276.7 pg/mL (+/- 49.9 pg/mL) compared to grade 1 (mean 153.10 pg/mL +/- 20.68 pg/mL). Serum S100A4 &amp; plasma Fibulin-2 cut-off values of 344.8 pg/mL &amp; 2500 pg/mL respectively have a 95% specificity for identifying patients with grade 2 tumours over grade 1. To improve the diagnostic accuracy of grade 1 vs grade 2 samples, we combined S100A4 and Fibulin-2 concentrations to achieve an improved AUC of 0.682, *p&amp;lt;0.05. CONCLUSIONS Serum S100A4 is significantly higher in grade 2 compared to grade 1 meningiomas (95% sensitivity; cut off 344.8 pg/mL). Combining S100A4 and the previously published Fibulin-2 improves the accuracy of predicting grade 2 meningiomas.
INVESTIGATING NOTCH1 PATHWAY COMPONENTS IN HISTONE 3.3 MUTANT PAEDIATRIC HIGH-GRADE GLIOMA
Authors: Emayanthi Emayakumaran, Anbarasu Lourdusamy, Robert Layfield, Farhana Haque
Journal: Neuro-Oncology (2023)

Abstract AIMS High-grade gliomas (HGG) in adults and children (paediatric high-grade glioma, pHGG) differ in molecular characteristics, despite having the same morphological features. Although pHGG has a low incidence, it contributes to 40% of all brain tumour death in childhood. Histone 3 (H3) mutation is a unique feature of pHGG. The understanding the pathophysiology of these tumour are important to develop more targeted therapy for these tumours. Our previous research has identified, increased activation of the Notch1 pathway in H3 mutated tumours. We have now explored the relationship between the Notch1 pathway components to H3 mutated pHGG. We hypothesised that The Notch1 pathway components (NICD1, HES1, HES5) are dysregulated in the Histone 3 mutant tumours in comparison to H3 wild type tumours. METHOD Protein expression analyses, immunofluorescence and microscopy and western blot experiments were per- formed, to assess the localization and expression of Notch1 pathway components (NICD1, HES1, HES5), using cultures H3.3 wildtype and H3.3 mutant cell lines. RESULTS The results show that Notch1 pathway expression differ between H3 mutant and H3 wild type tumours. CONCLUSIONS These results suggest that components of Notch1 pathway (HES1/HES5) are dysregulated, which may be driving tumour growth in this H3 mutated tumour. Therefore, we can explore Notch1 Pathway components as targeted therapeutic options.
M6A RNA MODIfiCATION AND A DRIVER OF CELLULAR PLASTICITY AND INTRA-TUMOURAL HETEROGENEITY IN GLIOBLASTOMA
Authors: Simon Deacon, Masar Radhi, Jonathan Rowlinson, Helen Knight, Dong-Hyun Kim, Stuart Smith
Journal: Neuro-Oncology (2023)

Abstract AIMS The immense cellular plasticity of glioblastoma is a barrier to successful therapy. N6-methyladenosine (m6A) methylation of RNA is increasingly recognised as a key driver of cellular differentiation. Crucially, it is a reversible and dynamic modification that alters cellular phenotype via the regulation of mRNA metabolism. We hypothesise that m6A methylation mediates glioblastoma plasticity, regulating transcriptional networks and thus influencing cellular adaptation under different microenvironmental conditions. Our aims are to assess whether total m6A levels and m6A-regulatory gene expression are responsive to change in oxygenation levels and cellular confluency. Furthermore, we aim to characterise the spatial distribution of m6A in 3D cell culture models. METHOD We have investigated m6A levels in patient-derived cell lines from the invasive region of adult glioblastoma. Mass spectrometry and anti-m6A immunofluorescence confocal microscopy was used to quantify total m6A levels. We have compared total m6A levels in normoxic versus hypoxic culture conditions and in low versus high confluency 2D cell culture, including cell migration during a scratch assay. We have measured expression levels of key m6A-regulatory genes using rtPCR. RESULTS Total m6A levels and regulatory gene expression were not significantly different in normoxic versus hypoxic conditions. However, m6A levels were decreased in high confluency versus low confluency conditions. We will further characterise the spatial distribution of m6A in 3D cell culture models using immunofluorescence confocal microscopy. CONCLUSIONS We demonstrate a degree of variability in m6A levels in response to micro-environmental conditions, such as cellular confluency. These findings indicate a role for m6A in tumoral heterogeneity and cellular adaptation.
FISH-BASED INVESTIGATION OF CDKN2A AND IFNA14 IN GLIOBLASTOMA
Authors: Sofian Al Shboul, Shelagh Boyle, Ashita Singh, Tareq Saleh, Moath AlRjoub, Ola Abu Al Karsaneh, Amel Mryyian, Rand Dawoud, Sinem Gul, Shaden Abu baker, Kathryn Ball, Ted Hupp, Paul Brennan
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) tumours have a dismal prognosis despite aggressive anticancer therapy. Deletion of CDKN2A is among the most common genetic changes in GBM (~50%) and has been strongly associated with worse prognosis. Next generation DNA sequencing had shown that deletion of IFNA genes (located proximal to CDKN2A) is also a major genetic event in GBM (~25%). Clinical Identification of in vivo state of these two genes might facilitate improved individualized therapeutics. METHOD Glioma tissue microarray consisting of 45 samples was used to assess the co-deletion of CDKN2A and IFNA14 genes simultaneously, using a novel three-color fluorescence in situ hybridization (FISH) probe. We examined the correlation between CDKN2A and p16INK4a protein expression detected using immunohistochemistry (IHC). RESULTS FISH analysis showed that 44% of the primary GBMs harboured homozygous deletions of both CDKN2a and INFA14. By contrast, all grade II and III gliomas, had either wild-type or amplified CDKN2A and INFA14. All samples that showed CDKN2A homozygous deletion (n=11) were negative for p16INK4a staining, while 20 cores that were positive for p16INK4a expression did not harbour CDKN2A deletion. Survival curves of primary GBMs suggested that both the co-deletion of CDKN2A/INFA14 and negative p16INK4a expression were associated with shorter survival time. CONCLUSIONS Our FISH/IHC analyses indicate a strong correlation between CDKN2A and p16INK4a protein expression in grade III/II glioma, suggesting that amplification of CDKN2A might act as a gatekeeper to reduce the incidence of grade IV. Our data also highlight the high frequency of CDKN2A/INFA14 co-deletion in GBM tumours that might together impact on survival time.
MULTI-OMICS MENDELIAN RANDOMISATION USING EXPRESSION, PROTEIN AND SPLICING QUANTITATIVE TRAIT LOCI: IDENTIfiCATION OF NOVEL DRUG TARGETS ASSOCIATED WITH RISK OF GLIOMAGENESIS
Authors: Zak Thornton, Lily Andrews, Huiling Zhao, Chris Zheng, Lavinia Paternoster, Jamie Robinson, Kathreena Kurian
Journal: Neuro-Oncology (2023)

Abstract AIMS Genetic variants associated with molecular traits are also associated with liability to glioma. We sought to pro- vide causal evidence for the prioritization of these traits using triangulation of several causal inference approaches. METHOD We performed two-sample Mendelian randomization and genetic colocalization of molecular traits on glioma. Molecular data were taken from studies of expression quantitative trait loci (QTL) [11,803 genes]; protein QTL [7,376 proteins] and splicing QTL [13,285 genes]) derived from 15 brain tissues. Glioma data were taken from a genome-wide association meta-analysis (12,496 cases and 18,190 controls). RESULTS The MR analysis showed evidence for a causal effect of 25 molecular traits on glioma. Of these, 19 (all gene expression) were robust according to colocalization and Steiger filtering. 18/19 (95%) of these genes were previously implicated in genome-wide and transcriptome-wide association studies with glioma risk. We identified one novel locus with causal evidence in cortex tissue: HBEGF (5q31.3). HBEGF expression has been found to be significantly increased in many human cancer types, including glioma. We found genetically predicted in- creased expression of HBEGF associated with an increased risk of all glioma [OR 1.53 (95%CI 1.28 to 1.82); P =2.66 x 10-6] and the glioblastoma subtype [OR 1.68 (95%CI 1.35 to 2.08); P = 2.97 x 10-6]. CONCLUSIONS We provide robust causal evidence as validation for genes previously implicated with glioma risk in genome- wide association studies. Additionally, we show for the first-time evidence for a causal relationship between HBEGF expression and glioma risk.
OUTCOMES OF STEREOTACTIC RADIOSURGERY/RADIOTHERAPY (SRST) IN MALIGNANT MELANOMA WITH CRANIAL METASTASES - THE WESSEX EXPERIENCE
Authors: Jonathan Ah-Chuen, Emma Johnson, Isobel Conibear, Ruth Carr, Eleni Simpson, Georges Sinclair, Enrico Clarke, Jeng Ching
Journal: Neuro-Oncology (2023)

Abstract AIMS To assess overall survival in malignant melanoma with cranial metastases following stereotactic radio- surgery/radiotherapy (SRST). METHOD Patients with metastatic melanoma who received SRST for their cranial metastases at the Wessex Neuro- Oncology Unit were evaluated between January 2017 and January 2023. Subtype analysis based on BRAF mutation was also performed. Their overall survival (OS) was plotted using Kaplan-Meier graph. RESULTS 121 patients were identified. The mean age at referral was 62 years (range 30-90). 50 patients had a BRAF mutation while 71 were BRAF wild type. This is a heterogenous cohort of patients, ranging from cranial-only disease to widespread disease, receiving one to two lines of systemic treatment. The median OS in patients with malignant melanoma with cranial metastases following SRST is 15 months (similar in both BRAF mutant and BRAF wildtype subgroups). The 3-year survival rate is 22.8% (BRAF mutant – 27.3%, BRAF wildtype - 20.3%). There is a small group of patients (28%) that died within six months of SRST. CONCLUSIONS Limitations were the small number of patients, short follow up period and heterogeneity in terms of systemic therapy. Our experience reveals in malignant melanoma, the median OS is 15 months after SRST to their cranial metastases. We found that BRAF mutation is non-discriminatory when predicting response to SRST and not the sole factor in predicting OS. A small cohort did not benefit from SRST as they survived for 6 months or less. Further analysis of this subgroup is needed to improve patient selection and treatment personalisation.